The AIDS virus is likely to claim tens of millions of lives by the year 2,000, constituting a worldwide health concern of top priority [see, DeVita, et al., AIDS, Etiology, Diagnosis, Treatment and Prevention, 3rd edition, J. B. Lippincott Co., Philadelphia, Pa. (1992); Wong-Staal, in Virology, pp 1529-1543; and Hirsch, et al., in Virology, pp. 1545-1570]. The design of an effective HIV vaccine poses a particular challenge to immunologists, as the reverse transcriptase enzyme involved in the replication of HIV has a high error rate. This results in many mutant HIV strains having outer coat or envelope proteins with variant protein sequences. These variant envelope proteins are often recognized as different antigens by the mammalian immune system, which produces more than 10.sup.9 new lymphocytes per day for the sole purpose of countering foreign antigens. B and T-cells constitute, respectively, the humoral and cellular components of the immune response.
A good example of the qualitative strength of such immune responses is shown in HIV-infected patients and in SIV-infected macaques. In each case, successive rounds of infection, immunity, and establishment of variant HIVs or SIVs occur [Wrin, et al., J. Acquir. Immune Defic. Syndr. 7:211-219 (1994); Burns and Desrosiers, Cur. Topics Microbiol. Immunol. 188:185-219 (1994)]. With each cycle, the diversity of HIV antigenic determinants (and the corresponding immune responses) are increased, such that these immune responses neutralize a broad range of SIV or HIV variants, and superinfection is largely inhibited.
However, AIDS patients develop compromised immune responses that become insufficient to prevent the HIV viral infection from overcoming the patient's immune system. This may be due in part to the establishment of HIV variants whose envelope variant proteins are not recognized by the patient's immune system and thus escape destruction (Sci. Amer. August 1995, pp ). In such cases, even if the immune response is capable of preventing de novo infection (e.g., persistent mutation of the virus in privileged sequestered sites), the HIV infection may ultimately overcome the patient's immune response [Pantaleo et al., Nature 362:355-358 (1993); Embretson, et al., Nature 362:359-362 (1993)].
The identification of B- and T-cell antigenic determinants among HIV proteins remains incomplete. The HIV envelope protein has been characterized as having variable (V1-V5) and constant (C1-C5) regions. A peptide representative of the V3 region has been termed the principal neutralizing determinant (PND) [Javaherian et al., Proc. Natl. Acad. Sci. (USA) 86:6768-6772 (1989)], although other regions of the envelope protein may also be involved in eliciting an immune response. The full length envelope protein from HIV contains about 850 to 900 amino acids, with the variation in length due to hypermutation [Starcich et al., Cell 45:637 (1986)].
The first vaccines against HIV evaluated in clinical trials were designed to present single envelope proteins, or portions thereof, to the immune system. However, neutralizing responses towards a single or a few envelope proteins did not recognize diverse isolates of HIV and the individuals were not protected from infection [Belshe et al., J. Am. Med. Assoc. 272:431-431 (1994); U.S. Pat. No. 5,169,763; PCT publication WO 87/06262; Zagury et al., Nature 332:728-731 (1988); Kieny et al., Int. Conf. AIDS 5:541 (1989); Eichberg, Int. Conf. AIDS 7:88 (1991); Cooney et al., Proc. Natl. Acad. Sci. USA 90:1882-1886 (1993), Graham et al., J. Infect. Dis. 166:244-252 (1992); J. Infect. Dis. 167:533-537 (1993); Keefer et al., AIDS Res. Hum. Retrovir. 10 (Suppl. 2):S139-143 (1994); Gorse, AIDS Res. Hum. Retrovir. 10 (Suppl. 2):141-143 (1994); McElrath et al., J. Infect. Dis. 169:41-47 (1994); Fauci, Science 264:1072-1073 (May 1994)].
Accordingly, there is a long-felt and pressing need to discover vaccines and methods that elicit an immune response that is sufficient to treat or prevent HIV infections.